PROJECT SUMMARY/ABSTRACT ? OVERALL This is a new application of a program project grant to the NHLBI by three investigators located within the College of Medicine of the Pennsylvania State University in Hershey, Pennsylvania. All investigators are highly productive scientists. All Project and Core Leaders are collaborative and all will greatly benefit from this program. We believe this application fulfills the criteria for a PPG because: 1) there is a unifying theme namely that the exercise pressor reflex (EPR) is accentuated in peripheral artery disease (PAD) and this accentuation has significant cardiovascular consequences. Two models of limb ischemia will be employed to explore this reflex: (a) PAD in human subjects (Project 1); and (b) hindlimb arterial occlusion in rats (Projects 2 and 3); 2) conceptual synergy exists between the projects that will lead to important advances in cardiovascular physiology and pathophysiology; 3) this PPG has broadly defined goals that can be accomplished within the 5 year funding period; and 4) many of the ideas and concepts proposed are a direct result of previous interactions between the project leaders. Dr. Sinoway will be the PPG Program Director (PD). He has substantial scientific and administrative experience, serving as the PD of the NIH funded Clinical and Translational Science Institute at Penn State, and PD of a PPG from 2004 to 2016. In Project 1, Dr. Sinoway will examine the cardiovascular consequences of an accentuated exercise pressor reflex in human subjects with PAD and intermittent claudication. He will examine the impact the accentuated reflex has on the peripheral and cardiac circulations. In Project 2, Dr. Li will examine the role pro-inflammatory cytokines play in altering the blood pressure response to hindlimb contraction after hindlimb arterial occlusion. He will also examine how pro-inflammatory cytokines alter signal transduction in DRG neurons of these animals. In Project 3, Dr. Kaufman will examine the role EP4, ASIC3 and P2X3 receptors on DRG neurons play in accentuating the pressor reflex to hindlimb contraction in rodents with hindlimb arterial occlusion. Two core laboratories are proposed; an Administrative (Core A) that will oversee all administrative functions and a Transfection Core Laboratory (Core B) that will design effective siRNA sequences and provide cDNA clones that code for these `short hairpin' nucleotide sequences, perform the in vivo and in vitro transfection of DRG (L4-L5) and gastrocnemius muscle, and verify protein knockdown employing quantitative RT-PCR (mRNA levels) and Western blotting (protein quantification).